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Stem Cell Transplant in Childhood Acute Lymphoblastic Leukemia
by
Kathryn Leung, M.D., and
Robert Krance,
M.D.
Chemotherapy
administered over a two to three year period results in long lasting remission
for the majority of children with acute lymphoblastic leukemia
(ALL). The disease-free survival (DFS) using conventional
chemotherapy can be as high as 90 percent. However, for some children
with high risk ALL there is little likelihood of cure with
chemotherapy alone. These high risk patients are characterized
by the presence of particular cytogenetic features such as
Philadelphia chromosome (Ph+) ALL, MLL gene mutations in infant
ALL and hypodiploid ALL. In addition, patients whose
induction response to chemotherapy is prolonged or children who
relapse despite receiving effective therapy cannot be dependably
salvaged by further conventional treatments.1, 2 For these
patients, stem cell transplant (SCT) is the only option for cure.
SCT offers no
advantage over chemotherapy for most children with ALL in first
complete remission as determined by 10 years DFS; children with
Ph+ ALL were notable exceptions. DFS for these patients
following standard chemotherapy treatment is 25 percent
compared to 70 percent DFS following matched sibling donor (MRD) SCT.1 Unfortunately,
for patients without a sibling donor, the DFS as reported has not
surpassed that achieved with chemotherapy. It is likely,
however, that the poorer outcome following MUD SCT reflect
registry, which is a compilation of results reported from many
centers. Outcome data from single centers often are better. For
example, at our own center, DFS for MUD SCT in Ph+ patients
transplanted in CR1 exceeds 60 percent, which is comparable to DFS for
MRD SCT.
When treated
with chemotherapy, infants diagnosed with ALL, in particular
those with the MLL gene mutation, t(4:11), have a very poor
prognosis (0 percent to 23 percent) compared to other children with ALL.4
Although some investigators do not find that transplantation
improves survival for patients, a recent study of 40 infants
with ALL, most with 11q23 mutation, reported 76 percent DFS at
three years
following transplantation from related and unrelated donors.5
Patients with
hypodiploid leukemia cells (modal number less than 45) also have
a poor prognosis for cure. Event free survival (EFS) at 5 years
was 20 percent in patients with hypodiploid leukemia compared to 75
percent in
those patients with leukemia cells having modal numbers greater
or equal to 45.6 Although the data are somewhat premature and
the numbers of transplanted patients with hypodiploid leukemia
are small, it is generally accepted that SCT in first remission
offers a reasonable opportunity for cure.
Relapsed ALL,
regardless of cytogenetic markers, conveys a poor prognosis. A
retrospective of 432 children who received either chemotherapy, autologous SCT or allogeneic SCT from MRD and unrelated donors
(MUD) showed that EFS were 28 percent in patients who received
maintenance chemotherapy or autologous SCT compared to 42
percent in
patients who received an allogeneic SCT after CR2. Although
initial reports suggested a role for autologous SCT in the
treatment of ALL, subsequent findings established autologous SCT
as no better than chemotherapy.
For patients
who relapse more than 12 months after completion of
chemotherapy, some have advocated salvage chemotherapy without
SCT, even when a matched related donor is available.
However, a large retrospective study demonstrated that
regardless of the duration of first remission, the DFS in
patients undergoing transplantation (36 percent) exceeded that of
patients treated with chemotherapy (17 percent). The risk of relapse
after transplantation was 45 percent compared to 80 percent in patients who
did not receive a transplant.8
Finally, a
number of reports indicate MUD SCT compares favorably to MRD SCT
as salvage therapy for children with relapsed ALL. One study
found DFS to be similar for MRD and MUD SCT, 81 percent and 73
percent
respectively. The similar outcomes are likely the product of
many advances in transplantation care including enhanced HLA
typing and better supportive care.9 Thus, there are data to
support the recommendation for SCT from MUD as well as MRD for
any child who has relapsed.
Given its
ability to cure children with high risk or advanced ALL, it is
unfortunate that some patients cannot undergo transplantation
because they lack suitable donors. For patients without an HLA
matched donor, alternative stem cell sources have been explored.
One potential source is parental haploidentical donors who
undergo GCSF stem cell mobilization and leukopharesis. Stem
cells then are separated from the collected product using CD34+
antibody, which selects a population of cells enriched for hematopoietic stem cells and excludes cells that would provoke
severe GVHD. A recent study of 26 patients with advanced ALL
resulted in DFS 44 percent for those transplanted in remission.
Besides
haploidentical-related donor source, another alternative stem
cell source is umbilical cord blood (UCB). Early reports on the
use of UCB (MRD and MUD with two or less HLA antigen disparities)
indicated comparable survival rates in patients with leukemia as
well as decreased incidence of graft vs. host disease (GvHD).
In patients with high risk ALL the DFS at two years for unrelated UCB SCT is 56
percent, comparable to bone marrow/peripheral blood stem
cell transplant. The disadvantages to UCB include prolonged
engraftment time and stem cell dose limitations.11, 16
To combat the
most prevalent cause of transplant failure (relapse),
active investigation has focused onto the role of anti-leukemia
conditioning therapy. Myeloablative conditioning regimens
consist of high dose chemotherapy and/or irradiation. The
backbones of these conditioning regimens include busulfan and/or
cyclophosphamide +/- high doses of hyperfranctionated
radiation totaling 10Gy to 14Gy. Several studies have shown that
regimens containing TBI have better EFS (40 percent) when compared to
chemotherapy based regimen (22 percent).12
For patients
with significant organ impairment, the use of reduced-intensity
preparative regimens has been investigated. These regimens vary
in their ability to myeloablate, immunoablate and produce an
anti-tumor effect. Toxicity varies between regimens but generally
is decreased when compared to intensive, myeloablative
regimens. Antitumor effect using reduced-intensity preparative
regimens rely on graft-versus-leukemia effect (GVL).
Unfortunately, there is little outcome data regarding efficacy
of subablative conditioning and GVL against ALL.13 Caution
toward this approach arises from the data collected after
administration of donor lymphocyte infusions (DLI) to patients
with ALL who have relapsed following SCT. Sustained anti-leukemic
responses have been far less for patients with ALL treated with DLI compared to that for patients with CML and AML.
Research into
novel therapies to combat very resistant ALL is ongoing. One
such therapy is to target proteins highly expressed on leukemia
cells. At our institution, we are investigating the use of
antiCD45 monoclonal antibodies in our preparative regimen to
enhance myeloreduction and to produce sustainable remission in
patients with highly resistant leukemia, including ALL.
While relapse
is the major cause of failure, treatment-related mortality
impacts overall outcome. To that end, prevention of post-transplant viral infection is a major goal. Several trials are
under way at our institution wherein eligible patients are
enrolled in studies using cytotoxic T lymphocytes targeted
against CMV, EBV and adenovirus reactivations. This approach is
based upon our prior experience using ex vivo donor-derived EBV-specific
CTLs to prevent EBVLPD following MUD or mismatched related donor
SCT. Once administered, EBV-specific T cells persisted in vivo
and were able to respond to antigenic challenge for up to 18
months.15 The longevity of the transferred EBV-specific CTL as
well as the persistent antigenic activity indicates that
antigen-specific CTLs may be applicable to other viruses such as
CMV and adenovirus. Infections caused by these agents plague
post-transplant patients, causing significant morbidity and
mortality.
In summary,
despite major strides in the treatment of childhood ALL, too
many patients fail standard chemotherapy and require more
rigorous treatment, such as SCT. Novel cellular targets to
improve DFS, immunotherapy to combat infections and improve post
transplant immunity, and improvements in HLA typing are active
areas of research to improve the outcome for patients with ALL
undergoing SCT. Continued research to improve transplant regimen
and reduce therapy related morbidities are ongoing.
About the authors
Kathryn Leung, M.D., is an assistant professor in pediatrics, subspecializing in hematology/oncology at Texas Children’s
Cancer Center. Her primary focus is on
stem cell transplant in children with bone marrow failure and hemoglobinopathies. She also is working with other investigators
in the Cell and Gene Therapy
Program to apply new therapies in
hopes of decreasing the morbidities from post-transplant viral
infections in SCT patients.
Robert Krance, M.D. is a professor of pediatrics at Baylor College of Medicine and director of the
Pediatric Stem Cell Transplant Program at the Texas Children's Cancer Center. Dr. Krance's research focuses on the development of
transplantation using alternative donors and less than fully HLA
matched related donors. In collaboration with other
investigators in the Cell and Gene Therapy Program, new
cell-based approaches are being conducted hopefully to diminish
the impact of viral infection post transplantation.
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